Structure–Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis

Discovery
of novel antitubercular drugs is an effective strategy
against drug-resistant tuberculosis (TB). Our previous study has identified LPX-16j as a novel antitubercular compound. Herein, we perform
a comprehensive structure–activity relationship (SAR) based
on LPX-16j, indicating that the central pyrimidine ring
moiety was crucial for the antitubercular activities of its derivatives,
and replacing the naphthyl group with hydrophobic substitutes was
well tolerated. The representative derivative 5a exhibited
potent activity against H37Ra, H37Rv, and clinical drug-resistant
TB with minimum inhibitory concentration (MIC) values of 0.5–1.0
μg/mL. Meanwhile, 5a showed an acceptable safety in vivo and displayed a favorable oral bioavailability with
a value of 40.7%. The differential scanning fluorescence, isothermal
titration calorimetry, and molecular docking assays indicated that
PknB could be one of the targets of compound 5a. Overall,
this study identified 5a as a novel promising lead compound
with the potential to develop candidates for the treatment of drug-resistant
TB.

抗结核新药的发现是应对耐药结核病（TB）的有效策略。我们此前的研究已将LPX-16j鉴定为新型抗结核化合物。本文基于LPX-16j开展了全面的构效关系（SAR）研究，结果显示其中央嘧啶环母核对其衍生物的抗结核活性至关重要，且以疏水取代基替换萘基具有良好的耐受性。代表性衍生物5a对H37Ra、H37Rv及临床耐药结核菌株均表现出强效活性，最低抑菌浓度（MIC）值为0.5~1.0 μg/mL。同时，5a在体内展现出良好的安全性，且口服生物利用度达40.7%。通过差示扫描荧光法、等温滴定量热法及分子对接实验，证实PknB可作为化合物5a的作用靶点之一。综上，本研究将5a鉴定为一种极具开发潜力的新型先导化合物，有望用于开发耐药结核病治疗候选药物。